The possibility that obesity-associated inflammatory changes may play a role in the pathogenesis of type 2 diabetes (2DM) has led to increased interest in the possibility that salicylates might represent a useful treatment to improve glucose tolerance. Several studies, performed in patients with 2DM, as well as in nondiabetic, obese individuals, have demonstrated that salicylates have beneficial effects on glucose and insulin metabolism, but have not led to a coherent view as to the mechanism(s) involved. Thus, both positive and negative information has been presented as to the effect of salicylates on insulin action, insulin secretion, and insulin clearance. The lack of consensus may result from the fact that none of these studies have used specific methods, in contrast to surrogate estimates, to quantify the effect of salicylate administration on all three relevant variables in the same study;insulin-mediated glucose uptake (IMGU), glucose-stimulated insulin secretion rate (GS-ISR), and insulin clearance (I-Cl). Furthermore, studies in obese, nondiabetic individuals have not taken into account the fact that approximately one-third of obese individuals are insulin sensitive, and it is difficult to demonstrate a benefice effect of any intervention on IMGU in such subjects. This research proposal represents an effort to overcome these confounders by using specific methods to quantify IMGU, GS- ISR, and I-Cl in overweight/obese, nondiabetic, insulin resistant individuals. We will use the insulin suppression test (IST) to quantify IMGU in nondiabetic, overweight/obese volunteers to identify those individuals who are sufficiently insulin resistant to be enrolled in this study. We will then use the graded glucose infusion technique in these insulin resistant subjects to generate specific measures of both GS-IS and I-Cl. Following these baseline measurements, salsalate or placebo will be administered for one month to the participants, after which time the IST and the graded glucose infusion will be repeated to quantify and compare the changes in IMGU, GS-ISR, and I-Cl that have resulted from salsalate versus placebo. These results will provide for the first time quantitative data of the effect of salicylates on IMGU, GS-ISR, and I-Cl in overweight/obese, insulin resistant, nondiabetic individuals. PUBLIC HEALTH RELEVANCE: Although there is evidence that salicylate administration may be useful in the treatment of patients with diabetes, there is no general agreement as how this beneficial effect occurs. In this study we will try to supply this missing information by using specific methods to compare in overweight/obese, insulin resistant, nondiabetic individuals the effects of salicylate versus placebo administration on insulin action, insulin secretion, and insulin clearance.